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Background
Combination therapies of anorectic gut hormones partially mimic the beneficial effects of bariatric surgery. Thus far, the effects of a combined chronic systemic administration of Glucagon-like peptide-1 (GLP-1) and peptide tyrosine tyrosine 3-36 (PYY\(_{3-36}\)) have not been directly compared to Roux-en-Y gastric bypass (RYGB) in a standardized experimental setting.
Methods
High-fat diet (HFD)-induced obese male Wistar rats were randomized into six treatment groups: (1) RYGB, (2) sham-operation (shams), (3) liraglutide, (4) PYY\(_{3-36}\), (5) PYY\(_{3-36}\)+liraglutide (6), saline. Animals were kept on a free choice high- and low-fat diet. Food intake, preference, and body weight were measured daily for 4 weeks. Open field (OP) and elevated plus maze (EPM) tests were performed.
Results
RYGB reduced food intake and achieved sustained weight loss. Combined PYY\(_{3-36}\)+liraglutide treatment led to similar and plateaued weight loss compared to RYGB. Combined PYY\(_{3-36}\)+liraglutide treatment was superior to PYY\(_{3-36}\) (p ≤ 0.0001) and liraglutide (p ≤ 0.05 or p ≤ 0.01) mono-therapy. PYY\(_{3-36}\)+liraglutide treatment and RYGB also reduced overall food intake and (less pronounced) high-fat preference compared to controls. The animals showed no signs of abnormal behavior in OF or EPM.
Conclusions
Liraglutide and PYY\(_{3-36}\) combination therapy vastly mimics reduced food intake, food choice and weight reducing benefits of RYGB.
A relevant issue on the treatment of adrenocortical carcinoma (ACC) concerns the optimal duration of adjuvant mitotane treatment. We tried to address this question, assessing whether a correlation exists between the duration of adjuvant mitotane treatment and recurrence-free survival (RFS) of patients with ACC. We conducted a multicenter retrospective analysis on 154 ACC patients treated for ≥12 months with adjuvant mitotane after radical surgery and who were free of disease at the mitotane stop. During a median follow-up of 38 months, 19 patients (12.3%) experienced recurrence. We calculated the RFS after mitotane (RFSAM), from the landmark time-point of mitotane discontinuation, to overcome immortal time bias. We found a wide variability in the duration of adjuvant mitotane treatment among different centers and also among patients cared for at the same center, reflecting heterogeneous practice. We did not find any survival advantage in patients treated for longer than 24 months. Moreover, the relationship between treatment duration and the frequency of ACC recurrence was not linear after stratifying our patients in tertiles of length of adjuvant treatment. In conclusion, the present findings do not support the concept that extending adjuvant mitotane treatment over two years is beneficial for ACC patients with low to moderate risk of recurrence.
Auswirkungen unterschiedlicher Haltungsbedingungen auf Phänotyp und Genexpression im Mausmodell
(2015)
In zahlreichen Untersuchungen konnte gezeigt werden, dass Umweltbedingungen im frühen Lebensalter einerseits die Entwicklung von Resilienz, d.h. Widerstandsfähigkeit gegenüber Stressoren, andererseits aber auch die Entwicklung physischer und psychischer Erkrankungen im weiteren Lebensverlauf beeinflussen können. Dabei wird angenommen, dass sich sowohl dezidiert positive als auch in Maßen aversive Umweltbedingungen mit rezidivierender Stressbelastung günstig auf die Resilienz im späteren Leben auswirken können. Auf neurobiologischer Ebene scheinen dabei das CRH und seine Rezeptoren (CRHR1 und CRHR2), das NPY-System sowie das NPS-System (insbesondere NPS-Rezeptor) eine besondere Rolle zu spielen. Jedoch sind die exakten Zusammenhänge und neurobiologischen Grundlagen weiterhin nur unzureichend aufgeklärt. Dies ist insbesondere insofern bedauernswert, da weiterer Erkenntnisgewinn auf diesem Gebiet möglicherweise Präventionsstrategien und Therapieoptionen für den Menschen begründen könnte. Um die Auswirkung der Umweltbedingungen im frühkindlichen Lebensalter auf die Resilienz im späteren Leben weiter aufzuklären, wurden im Rahmen dieser Arbeit insgesamt 310 Cd1-Mäuse den Haltungsbedingungen "Environmental Enrichment" (EE, Stimulation durch Spielobjekte) und "Maternal separation" (MS, wiederholte Stressbelastung durch Separation der Nachkommen vom Muttertier) sowie Standardhaltungsbedingungen unterworfen. Insgesamt 31 männlichen Tieren wurde im Alter von vier Wochen die Gehirne entnommen und aus diesen jeweils die Regionen Frontalcortex,
Striatum, Nucleus accumbens, Hippocampus, Amygdala, dorsale Nuclei raphes und Hypothalamus herauspräpariert. Aus den gewonnenen Proben wurde RNA extrahiert, hieraus cDNA synthetisiert und abschließend - nach Ausschluss von Kontamination und Integritätsprüfung - die Expressionsraten der untersuchten Gene mittels RT-qPCR quantifiziert. Um auch verhaltensbiologische Konsequenzen der unterschiedlichen Haltungsbedingungen zu erfassen, wurden außerdem 30 weibliche sowie 30 männliche Tiere im weiteren Lebensverlauf verschiedenen Verhaltenstests zugeführt. In den Sucrose-Präferenz-Tests zeigten sich Effekte der Haltungsbedingung auf Sucrose-Konsum und Präferenz mit signifikant geringeren Werten der Haltungsgruppe EE. Bei der Auswertung der Openfield-Tests fanden sich Gruppen-Geschlechter-Interaktionseffekte mit signifikant geringeren Werten (Gesamtstrecke, Strecke und Aufenthaltsdauer im zentralen Bereich, Eintritte in den zentralen Bereich) der weiblichen EE-Tiere. In den Barnes Maze-Tests benötigten die Tiere
der Haltungsgruppe EE an den meisten Testtagen signifikant weniger Zeit, um in die Escape-Box zu "entkommen". Auf neurobiologischer Ebene fanden sich signifikante Unterschiede der CRH-Expressionsraten in Amygdalae und Frontalcortex, der CRHR 1-Expressionsraten in Amygdalae und Hypothalamus sowie der CRHR2-Expressionsraten in Amygdalae und Hippocampus. Demgegenüber konnte kein signifikanter Effekt der Haltungsbedingung auf das NPY-System gefunden werden.
Jedoch ließen sich signifikante Unterschiede der NPSR1-Expressionsraten in Amygdalae, Frontalcortex, dorsalen Nuclei raphes und Hypothalamus feststellen. Es kann also grundsätzlich von Auswirkungen unterschiedlich aversiver Haltungsbedingungen auf die Stress-Resilienz von Versuchstieren ausgegangen werden. Dies ist einerseits für Tierversuche allgemein von grundsätzlicher Bedeutung. Andererseits legen die Resultate eine entsprechende frühkindliche "Programmierung" auch im Menschen nahe.
Sensitization to the adipokine leptin is a promising therapeutic strategy against obesity and its comorbidities and has been proposed to contribute to the lasting metabolic benefits of Roux-en-Y gastric bypass (RYGB) surgery. We formally tested this idea using Zucker fatty fa/fa rats as an established genetic model of obesity, glucose intolerance, and fatty liver due to leptin receptor deficiency. We show that the changes in body weight in these rats following RYGB largely overlaps with that of diet-induced obese Wistar rats with intact leptin receptors. Further, food intake and oral glucose tolerance were normalized in RYGB-treated Zucker fatty fa/fa rats to the levels of lean Zucker fatty fa/+ controls, in association with increased glucagon-like peptide 1 (GLP-1) and insulin release. In contrast, while fatty liver was also normalized in RYGB-treated Zucker fatty fa/fa rats, their circulating levels of the liver enzyme alanine aminotransferase (ALT) remained elevated at the level of obese Zucker fatty fa/fa controls. These findings suggest that the leptin system is not required for the normalization of energy and glucose homeostasis associated with RYGB, but that its potential contribution to the improvements in liver health postoperatively merits further investigation.
Background
Although surgery is considered the first-line treatment for patients with endogenous Cushing’s syndrome (CS), medical therapy is often required to control severe hypercortisolism. Metyrapone and osilodrostat are both steroidogenic inhibitors targeting the 11β-hydroxylase, however, their therapeutic effectiveness has not yet been directly compared. This study aimed to evaluate metyrapone and osilodrostat in the short-term therapy of CS.
Methods
Retrospective analysis of patients with endogenous CS treated with metyrapone or osilodrostat as monotherapy for at least 4 weeks. Main outcome measures were serum cortisol and 24h urinary free cortisol (UFC) at baseline (T0) and after 2 (T1), 4 (T2), and 12 weeks (T3) of therapy.
Results
16 patients with endogenous CS were identified (pituitary n=7, adrenal n=4, ectopic CS n=5). Each 8 patients were treated with metyrapone and osilodrostat. Despite heterogeneity, both groups showed comparable mean UFC levels at T0 (metyrapone: 758 µg/24h vs osilodrostat: 817 µg/24h; p=0.93). From T0 to T1, the decrease of UFC was less pronounced under metyrapone than osilodrostat (-21.3% vs -68.4%; median daily drug dose: 1000 mg vs 4 mg). This tendency persisted at T2 (-37.3% vs -50.1%; median drug dose: 1250 mg vs 6 mg) while at T3 a decrease in UFC from T0 was more pronounced in the metyrapone group (-71.5% vs -51.5%; median dose 1250 mg vs 7 mg). Under osilodrostat, a QTc-interval prolongation was identified at T3 (mean 432 ms vs 455 ms). From T0 to T2, the number of antihypertensive drugs remained comparable under metyrapone and decreased under osilodrostat (n= -0.3 vs n= -1.0).
Conclusion
Although both drugs show comparable therapeutic efficacy, osilodrostat seems to reduce cortisol levels and to control blood pressure faster.
Background: Eosinophils appear to contribute to the efficacy of immunotherapy and their frequency was suggested as a predictive biomarker. Whether this observation could be transferred to patients treated with targeted therapy remains unknown. Methods: Blood and serum samples of healthy controls and 216 patients with advanced melanoma were prospectively and retrospectively collected. Freshly isolated eosinophils were phenotypically characterized by flow cytometry and co-cultured in vitro with melanoma cells to assess cytotoxicity. Soluble serum markers and peripheral blood counts were used for correlative studies. Results: Eosinophil-mediated cytotoxicity towards melanoma cells, as well as phenotypic characteristics, were similar when comparing healthy donors and patients. However, high relative pre-treatment eosinophil counts were significantly associated with response to MAPKi (p = 0.013). Eosinophil-mediated cytotoxicity towards melanoma cells is dose-dependent and requires proximity of eosinophils and their target in vitro. Treatment with targeted therapy in the presence of eosinophils results in an additive tumoricidal effect. Additionally, melanoma cells affected eosinophil phenotype upon co-culture. Conclusion: High pre-treatment eosinophil counts in advanced melanoma patients were associated with a significantly improved response to MAPKi. Functionally, eosinophils show potent cytotoxicity towards melanoma cells, which can be reinforced by MAPKi. Further studies are needed to unravel the molecular mechanisms of our observations.
Background: Treatment options for NAFLD are still limited. Bariatric surgery, such as Roux-en-Y gastric bypass (RYGB), has been shown to improve metabolic and histologic markers of NAFLD. Glucagon-like-peptide-1 (GLP-1) analogues lead to improvements in phase 2 clinical trials. We directly compared the effects of RYGB with a treatment using liraglutide and/or peptide tyrosine tyrosine 3-36 (PYY\(_{3-36}\)) in a rat model for early NAFLD. Methods: Obese male Wistar rats (high-fat diet (HFD)-induced) were randomized into the following treatment groups: RYGB, sham-operation (sham), liraglutide (0.4 mg/kg/day), PYY\(_{3-36}\) (0.1 mg/kg/day), liraglutide+PYY\(_{3-36}\), and saline. After an observation period of 4 weeks, liver samples were histologically evaluated, ELISAs and RNA sequencing + RT-qPCRs were performed. Results: RYGB and liraglutide+PYY\(_{3-36}\) induced a similar body weight loss and, compared to sham/saline, marked histological improvements with significantly less steatosis. However, only RYGB induced significant metabolic improvements (e.g., adiponectin/leptin ratio 18.8 ± 11.8 vs. 2.4 ± 1.2 in liraglutide+PYY\(_{3-36}\)- or 1.4 ± 0.9 in sham-treated rats). Furthermore, RNA sequencing revealed a high number of differentially regulated genes in RYGB treated animals only. Conclusions: The combination therapy of liraglutide+PYY\(_{3-36}\) partly mimics the positive effects of RYGB on weight reduction and on hepatic steatosis, while its effects on metabolic function lack behind RYGB.
Background: The hypothalamus is an important brain region for the regulation of energy balance. Roux-en-Y gastric bypass (RYGB) surgery and gut hormone-based treatments are known to reduce body weight, but their effects on hypothalamic gene expression and signaling pathways are poorly studied. Methods: Diet-induced obese male Wistar rats were randomized into the following groups: RYGB, sham operation, sham + body weight-matched (BWM) to the RYGB group, osmotic minipump delivering PYY3-36 (0.1 mg/kg/day), liraglutide s.c. (0.4 mg/kg/day), PYY3-36 + liraglutide, and saline. All groups (except BWM) were kept on a free choice of high- and low-fat diets. Four weeks after interventions, hypothalami were collected for RNA sequencing. Results: While rats in the RYGB, BWM, and PYY3-36 + liraglutide groups had comparable reductions in body weight, only RYGB and BWM treatment had a major impact on hypothalamic gene expression. In these groups, hypothalamic leptin receptor expression as well as the JAK–STAT, PI3K-Akt, and AMPK signaling pathways were upregulated. No significant changes could be detected in PYY3-36 + liraglutide-, liraglutide-, and PYY-treated groups. Conclusions: Despite causing similar body weight changes compared to RYGB and BWM, PYY3-36 + liraglutide treatment does not impact hypothalamic gene expression. Whether this striking difference is favorable or unfavorable to metabolic health in the long term requires further investigation.